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Threshold Pharmaceuticals Inc. Message Board

  • triad33 triad33 Mar 11, 2012 11:23 AM Flag

    I'll be there in the audience on Wednesday

    I have set up my meeting registration and travel itinerary for Wednesday, and I will be in the audience at the NY Academy of Science symposium on "Therapeutic and Diagnostic Modalities Targeting Hypoxia in Cancer" (Wednessday March 14th, 1:00-5:00 pm). I was able to get non-stop round trip flights, and I'll be coming up just for the day. I consider this NYAS event to be historic and do not want to miss being there in-person. Any other THLD investors planning on attending? We can sit together. This event is at 7 World Trade Center, in the heart of Lower Manhattan's financial district, and that is no coincidence.

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    • Curious, why do you think this will be so important or historic, seems like a typical general conference on the topic of hypoxia. Nothing out of the ordinary and i dont anticipate any additional data being presented here. The real data or the breakout data from the p2 trial will occur in April...

      • 1 Reply to pharmajedi
      • There are other things besides data and timing to factor in. This is not just a run-of-the-mill conference on hypoxia-targeted therapies. It is the first of its kind centered on something that actually works, for one thing. The location and participants do mean a lot here. NY Academy of Sciences is the premiere local scientific organization in the country. Siemens imaging technology is also important for the Ph 3 trial. Also, THLD's placement in the schedule says something too. The other participants deferred to CEO Selick on this.

    • Triad, thanks for attending. From what I've seen of your comments since I started my investment in THLD you have demonstrated a proficient knowledge of this science. Having you there to interpret the presentations for us novices will be extremely helpful. The future for THLD and their drug is very positive and I look forward to the next few weeks with excitement.

    • Triad33 - I am happy to see a few intelligent comments on this site, there are way too many morons. Happy as well that you are attending! This event is very prestigious and all the major players will be there listening, especially Merck. Listen carefully to their discussion on "drug combination testing" . Of special note, Merck owns interferon (cancer drug that seems to work better in combination with others) i.e azt and interferon for aids. Interferon has not been commercial as a stand alone.

      • 1 Reply to memphismutt63
      • It is interesting that you bring up interferons. Actually, Merck-Serono's (Merck KGaA's pharmaceutical subsidiary "German Merck") work with the interferons is centered on Rebif. This is a specific type of interferon (Interferon beta-1a), which is targeted at autoimmune suppression for treating multiple sclerosis. The other Merck (Merck & Co. or MSD--"American Merck" based in Whitehouse Station, NJ) markets SYLATRON (pegylated interferon alpha-2b). It is this other form of interferon that has applications in immune cell activation for cancer, especially for treating leukemia and melanoma. "American Merck" and "German Merck" are unrelated companies and they are also fierce competitors, having been totally divested from one another as a part of the reparations for World War I. It is ironic that that this NYAS meeting is held in "American Merck's" backward, just across the Hudson River (Roche's backyard too for that matter). Actually, Roche is the Interferon-king. Remember that half of the U.S. market for TH-302 is still dangling out there and Threshold really needs a U.S. partner to capitalize on that. There is no way that this company of 36 employees is going to be manufacturing and launching TH-302 on their own within a few years. I do not see the two Merck's coming together on this, but anything is possible, I guess.

    • "Selective Targeting of Hypoxic Cancer Cells with the Hypoxia-activated Prodrug TH-302: Preclinical and Clinical Studies"

      Charles P. Hart, PhD, Threshold Pharmaceuticals


      Hypoxic subregions are a prevalent feature of solid tumors, and have also been shown to exist in the diseased bone marrow of hematological malignancies. Tumor hypoxia is associated with poorer clinical prognosis. This is directly related to more rapid treatment failure (chemotherapy, radiotherapy) and the hypoxic induction of a more aggressive, invasive, and metastatic cancer phenotype. The low oxygen concentration in hypoxic tumor cells also allows their selective targeting via hypoxia-activated cytotoxic prodrugs (HAPs). TH-302 is a 2-nitroimidazole triggered bromo-isophosphoramide mustard that upon release causes DNA cross-linking and cell death in a hypoxia-selective manner in both human tumor cell lines in vitro and in human tumor xenografts in vivo. TH-302 was designed with a specific pharmacologic profile for an optimized HAP, including tissue penetrability, specific oxygen concentration dependence for activation, low susceptibility to metabolic inactivation and a bystander effect. TH-302 has been investigated in over 600 patients and is currently in Phase 1, Phase 2, and Phase 3 clinical trials. These include TH-302 monotherapy, combinations with conventional chemotherapeutics and combinations with molecularly targeted anti-angiogenic therapies known to induce hypoxia. Single agent activity was reported in the initial monotherapy study with tumor responses in patients with metastatic melanoma, SCLC and head and neck cancer. Development in soft tissue sarcoma is the most advanced with a randomized controlled Phase 3 trial comparing doxorubicin versus doxorubicin + TH-302 initiated in 2011. The specific contribution of TH-302 in combination therapy was demonstrated in a randomized controlled Phase 2b trial comparing gemcitabine versus gemcitabine + TH-302 in first-line advanced pancreatic cancer. The top-line results from this latter trial demonstrated a significant improvement (p=0.005, logrank test) in progression-free survival (PFS) with a median PFS of 3.6 months for patients treated with gemcitabine alone compared to 5.6 months for patients treated with gemcitabine + TH-302 groups and hazard ratio of 0.61(95% CI: 0.43 – 0.87). The response rate in the combination groups was 22% versus 12% in the gemcitabine alone group. TH-302 exhibits an attractive safety profile with TH-302 related skin and mucosal toxicities that are generally not dose limiting and associated myelosuppression that may be dose limiting in combination with cytotoxics. Taken together, the preclinical and emerging clinical results show that TH-302 can be administered safely in combination with the full dose conventional chemotherapeutics and that TH-302 as a monotherapy and in combination exhibits encouraging efficacy in a variety of solid tumors types.

    • Note that Harold Selick will be there, but Threshold's presentation will be made by one of its chief scientists, Charles Hart (Vice President, Biology):


      Charles P. Hart, PhD

      Threshold Pharmaceuticals

      Charles Hart joined Threshold Pharmaceuticals in 2004 and became Vice President of Biology in 2008. He is responsible for both in vitro and in vivo preclinical translational studies. Prior to joining Threshold he was Senior Director of Biology at Galileo Pharmaceuticals from 2001 to 2004, Director of Drug Discovery at Signature Bioscience from 2000 to 2001, and a Research Unit Director at Affymax (a Glaxo company) from 1990 to 2000. Charles received his A.B. in cell biology from the University of California at Berkeley in 1977, an M.S. in developmental biology from Stanford University in 1980, and a Ph.D. in molecular biology and genetics from Yale University in 1987. Charles completed a postdoctoral fellowship at the University of Strasbourg, France.

    • Regions of low oxygen concentration (hypoxia) within solid tumors are a prevalent feature of the cancer phenotype. Both chronic (diffusion-limited) and acute (perfusion-limited) tumor hypoxia have been described and both types of tumor hypoxia are due to abnormal aspects of tumor vasculature. The extent and magnitude of tumor hypoxia has been shown in multiple clinical studies to be a negative prognostic factor for survival. This is thought to be due to two key factors: (a) hypoxic tumor cells are able to resist conventional chemo- and radiation-therapies; and (b) hypoxic tumors are more invasive and metastatic. Transformation into a more invasive and metastatic tumor phenotype is believed to be driven by hypoxia-induced (a) genetic and epigenetic changes; (b) resistance to apoptosis; (c) induction of growth and survival factors; (d) increase in the production of extracellular matrix degrading enzymes that promote invasiveness and migration; (e) maintenance of cancer stem cell identity; (f) induction of the epithelial-mesenchymal transition (EMT); and (g) induction of angiogenesis and neovascularization. Hypoxia has also been shown to be associated with hematological malignancies and the bone marrow niches of leukemia and multiple myeloma. Hypoxic tumor cells are increasingly thought to be an attractive target for the discovery and development of novel cancer therapies; tumor hypoxia plays a central role in cancer progression and treatment resistance, and it provides a basis for selective targeting of tumor cells while sparing normoxic cells elsewhere in the body. A very promising therapeutic strategy is the use of hypoxia-activated prodrugs (HAPs), which enable the selective delivery of cytotoxic or cytostatic agents to hypoxic tumor cells. Furthermore, the development of non-invasive techniques for imaging tumor hypoxia (through PET and EPRI/MRI-based imaging approaches) will allow patient selection to identify those most likely to benefit from HAP therapy. The objective of this symposium is to provide a review of recent highlights in the study of the role of hypoxia in cancer, current advances in the discovery and development of drugs selectively targeting hypoxic cancer cells, and patient profiling approaches employing imaging or circulating or tissue biomarkers of hypoxia.

    • Note that Dr. Hart's (Threshold's) talk will be the last one in this symposium (generally considered a position of honor in a short scientific symposium of this sort):

      The New York Academy of Sciences
      7 World Trade Center
      250 Greenwich Street, 40th floor
      New York, NY 10007-2157
      212.298.8600


      Wednesday, March 14, 2012

      12:30 PM Registration

      1:00 PM Welcome and Introduction
      Jennifer Henry, PhD, The New York Academy of Sciences
      George Zavoico, PhD, MLV

      1:10 PM A Critical Evaluation of Methods for Imaging Tumor Hypoxia
      Mark W. Dewhirst, DVM, PhD, Duke University Medical Center

      1:50 PM Targeting Hypoxic Cell Signaling for Cancer Therapy
      Giovanni Melillo, MD, Bristol-Myers Squibb

      2:30 PM Molecular Imaging of Hypoxia
      Hartmuth C. Kolb, PhD, Siemens Healthcare USA

      3:10 PM Coffee Break

      3:40 PM NLCQ-1 (NSC 709257): A Weak DNA-intercalating Bioreductive Agent. An Overview and New Prospects
      Maria V. Papadopoulou, PhD, NorthShore University HealthSystem, University of Chicago

      4:20 PM Selective Targeting of Hypoxic Cancer Cells with the Hypoxia-activated Prodrug TH-302: Preclinical and Clinical Studies
      Charles P. Hart, PhD, Threshold Pharmaceuticals

      5:00 PM Networking Reception

      6:00 PM Program Ends

 
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